A molecularly defined recurrent CA3 circuit regulates network dynamics and spatial working memory

Abstract

The hippocampal CA3 region supports coordinated network activity and memory processes, but how molecularly distinct CA3 neuronal populations contribute to recurrent circuit function remains poorly understood. Here we identify St18 as a molecular marker of a distinct population of deep-layer, burst-firing CA3 pyramidal neurons and generate an St18-Cre mouse line for their selective genetic targeting. In contrast to canonical CA3 pyramidal neurons, St18 neurons preferentially innervate CA3 bilaterally, with only sparse projections to CA1. Moreover, St18 neurons are highly active during endogenous CA3 sharp-wave ripples, and their optogenetic activation evokes local ripple-like activity in CA3 but not in CA1. Furthermore, chemogenetic suppression markedly reduces CA3 ripple occurrence without significantly affecting CA1 ripple occurrence and selectively impairs spatial working memory performance. Together, these findings reveal the functional significance of a molecularly defined CA3 recurrent circuit, linking neuronal heterogeneity to hippocampal network dynamics and spatial working memory.